(Philadelphia, PA) - Researchers at the University of Pennsylvania
School of Medicine have found that the neurotransmitter norepinephrine
is essential in retrieving certain types of memories. This represents the first
description of a molecule implicated in recalling memories as opposed to laying
down new memories. Teasing apart different components of this pathway may help
physicians better understand post-traumatic stress disorder (PTSD) and depression
-- both of which involve alterations in memory retrieval, says lead author Steven
A. Thomas, MD, PhD, Assistant Professor of Pharmacology. The findings
of this research appear in the April 2 issue of Cell.

Using mutant mice lacking norepinephrine and rats treated with drugs that block
some norepinephrine receptors (beta blockers), the research team found that
this neurotransmitter is critical for retrieving intermediate-term contextual
and spatial memories, but not for the formation or long-term consolidation of
emotional memories, as previously hypothesized by others.

Mice and rats went through learning tasks that employ different brain regions:
the hippocampus, which governs spatial and contextual memories; and the amygdala,
which is important for emotional learning and memory in general.

The results of their tests ran counter to currently held hypotheses that suggest
that stress hormones like norepinephrine are responsible for enhanced memory
formation during emotionally arousing times. “Indeed, we set out to test
that hypothesis with our norepinephrine-deficient mice,” says Thomas.
“We expected to see a difference in amygdala-dependent behaviors between
the mutants and controls if it were emotional memory, in general, that was being
affected by the absence of norepinephrine. But we didn’t see that. Instead,
we found a specific impairment in hippocampus-dependent contextual memory retrieval.”

Using rats given beta blockers and a swimming navigation task in a water maze,
which
relies on the hippocampus but not the amygdala, the researchers sought to determine
if norepinephrine was also necessary for spatial memories. The tests indicated
that norepinephrine is critical for a period of time after a memory is formed,
but is not critical in recalling older memories. “There are probably other
mechanisms important for retrieving memories for the longer term that are independent
of norepinephrine,” says Thomas.

This line of research may have relevance to human learning and memory. Patients
suffering from post-traumatic stress disorder have recurrent intrusive memories;
that is, they experience traumatic events from the past in their minds. Evidence
from studies in other labs suggests that in PTSD there might be hyper-signaling
by norepinephrine. “Perhaps that’s one reason why PTSD patients
experience these recurrent intrusive memories,” says Thomas.

Depression may include the opposite problem in that there’s often difficulty
in memory retrieval, and this could be due, in part, to dysfunction of the adrenergic
system. In addition, beta-blockers, which are used to treat heart failure and
hypertension (among other ailments) block the same norepinephrine receptors
important for memory retrieval. Therefore, when treating heart disease, the
use of beta blockers that do not cross into the brain may help to avoid memory-related
side effects, suggest the researchers.

Other Penn researchers collaborating on this work are Charles F. Murchison,
Xiao-Yan Zhang, Wei-Ping Zhang, Ming Ouyang, and Anee Lee. The research was
supported in part by grants from the National Institutes of Health, the National
Alliance for Research on Schizophrenia and Depression, and the Mental Retardation
and Developmental Disabilities Research Center at the Children’s Hospital
of Philadelphia. The authors have no competing financial interest in this work.

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